More than 2 million Americans suffer from lupus, a widespread and life-long autoimmune disease. The detrimental role of B lymphocytes in lupus is evidenced by high levels of pathogenic antinuclear autoantibodies (ANAs) found in the patients. Suppression of autoantibody production by B cells has been considered as a therapeutic strategy for lupus. In addition, myeloid cells, in particular macrophages and neutrophils, contribute significantly to lupus development and lupus progression by producing pro-inflammatory cytokines and chemoattractant factors. Either blocking myeloid cell trafficking or suppressing their ability in producing inflammatory cytokines can reduce the clinical symptoms of lupus in both animal models and human patients. We have shown that inositol-requiring enzyme 1 alpha (IRE1?), the primary Unfolded Protein Response (UPR) transducer, is required for B cell differentiation into plasma cells. More recently, we discovered that inhibition of IRE1? suppressed inflammatory cytokine production by macrophages and neutrophils and protected mice from inflammatory arthritis. Further, we have obtained provocative preliminary evidence that the IRE1?-mediated UPR pathway is elevated in the peripheral leukocytes from lupus patients. Through both genetic and pharmacological approaches, we found that IRE1? is required for B cell differentiation into plasma and autoantibody production in the Lupus animal model, suggesting that IRE1? represents a unique, high-efficient therapeutic target for lupus. Additionally, we have identified a specific, non-toxic IRE1? inhibitor, 4?8c, which can efficiently suppress antibody production by B cells and pro-inflammatory cytokine production by macrophages and neutrophils. Based on our recent discoveries and preliminary studies, we propose that suppression of IRE1? can repress production of both auto-antibodies by plasma cells and pro-inflammatory cytokines by macrophage/neutrophil and thus protect from the development of lupus. The current proposed study is to use both genetic and pharmacological approaches to evaluation the pre-clinical therapeutic efficacy of IRE1? suppression in lupus treatment (Aim 1) and to delineate the underlying molecular mechanisms of IRE1? in promoting autoantibody production by B cells (Aim 2) and pro-inflammatory cytokine production by myeloid cells (Aim 3) during lupus development. The proposed studies will not only demonstrate a novel therapeutic strategy and a potential drug for lupus, but will also contribute to a better understanding of the molecular basis underlying autoimmune responses associated with auto-antibodies and pro-inflammatory cytokines.